Serum calcium is associated with sudden cardiac arrest in stroke patients from ICU: a multicenter retrospective study based on the eICU collaborative research database

This primary objective of our study was to investigate the relationship between serum calcium levels and the occurrence of sudden cardiac arrest (SCA) in stroke patients. We analyzed the clinical data of 10,423 acute stroke patients admitted to the intensive care unit. The association between serum calcium and SCA following an acute stroke was assessed through multivariate logistic regression. We explored the non-linear connection between serum calcium levels and SCA in stroke patients using a generalized additive model and smooth curve fitting. Our study uncovered that serum calcium serves as an independent risk factor for sudden cardiac arrest in stroke patients. Notably, we observed that the relationship between serum calcium levels upon admission and the occurrence of SCA in stroke patients within the hospital was non-linear. Furthermore, we identified inflection points in serum calcium levels at 8.2 and 10.4 mg/dL. These findings emphasize a non-linear relationship between serum calcium levels and the risk of SCA in stroke patients. Maintaining serum calcium within the range of 8.2–10.4 mg/dL could lead to a significant reduction in the incidence of cardiac arrest among stroke patients.

www.nature.com/scientificreports/Although intracellular calcium's role in cardiovascular physiology is well-established, the relationship between serum calcium levels and the development of arrhythmias and SCA is not well-defined.
The reference range for serum calcium falls within 8.9 to 10.1 mg/dL and is tightly regulated.Disturbances in calcium homeostasis can lead to various cardiovascular diseases.Hypercalcemia can result in QT interval prolongation, vascular calcification, and hypertension, while hypocalcemia can lead to life-threatening cardiac arrhythmias, cardiac arrest, heart failure, and prolonged QT intervals 8 .In Yarmohammadi et al. 10 reported for the first time that low serum calcium levels are independently associated with an increased risk of SCA in the general population.Their multivariate analysis demonstrated a 2.3-fold increase in SCA risk for individuals with lower serum calcium levels compared to those with higher levels.Other studies have highlighted the link between dyscalcemia and the risk of cerebrovascular diseases, with hypocalcemia and hypercalcemia associated with an increased risk of stroke [11][12][13] .Additionally, serum calcium levels have been linked to infarct size, stroke outcomes, recurrence of ischemic stroke, and prognosis in stroke patients, suggesting that serum calcium may serve as a potential prognostic biomarker for stroke 14 .
A recent study also found a connection between serum calcium levels and the risk of stroke-associated infection (SAI), with the risk of SAI increasing as serum calcium levels fall below normal (9.0 mg/dL) 15 .Despite these findings, the value of serum calcium in predicting acute stroke-related SCA remains uncertain.Currently, blood calcium regulation in stroke patients relies heavily on the clinical experience of physicians.Therefore, this retrospective study aims to investigate the association between serum calcium levels and acute stroke-related SCA, offering valuable insights for the prevention and treatment of post-stroke cardiac arrest.

Stratification of stroke severity in stroke patients
GCS follows a non-normal distribution, ranging from 3 to 15, with a median of 14 (Fig. 1).According to the GCS scores of stroke patients, we define GCS 13-15 as mild stroke with mild symptoms, GCS 9-12 as moderate stroke with moderate symptoms, and GCS 3-8 as severe stroke with severe symptoms, possibly accompanied by coma.Our results showed a severe stroke patient ratio of 15.8%.Most patients were classified as mild cases (Fig. 2).

Factors influencing the risk of SCA in stroke patients by univariate analysis
As shown in Table 2, univariate analyses showed that serum calcium, ionized calcium and ACSC was associated with in-hospital SCA in stroke patients (P < 0.05).Similar results were found for age, levels of Hb, RBC, Scr, BUN, Mg, GCS, ACS, CHF, hypertension (all P < 0.05).However, in-hospital SCA was not associated with sex, BMI, AF, cancer, hypertension (all P > 0.05).

Relationship between serum calcium and SCA in stroke patients in different models
As shown in Table 3 and Supplementary Table 2, several risk factors including important clinical and significant variables in the univariate model were included in the multivariate model for adjustment.Serum calcium remained an independent predictor of in-hospital SCA in adjusted Model 1 (OR 0.65, 95% CI 0.58-0.74,P < 0.001) and Model 2 (OR 0.79, 95% CI 0.66-0.94,P < 0.001).Similarity, ACSC remained an independent predictor of in-hospital SCA in adjusted Model 1 (OR 0.61, 95% CI 0.53-0.70,P < 0.001) and Model 2 (OR 0.79, 95%CI 0.66-0.94,P = 0.0084).

Non-linear relationship of serum calcium with SCA in stroke patients
To further explore the relationship between serum calcium and the incidence of in-hospital cardiac arrest in stroke patients, we plotted the smoothing curves of serum calcium against the incidence of in-hospital cardiac arrest in stroke patients.Smoothing splines were generated utilizing a generalized additive model and adjusted for age, sex, ethnicity, AF, CHF, ACS, COPD, diabetes, hypertension, GCS, Hb, Scr, and ALB.The results showed that the link between serum calcium and the incidence of in-hospital cardiac arrest was nonlinear (U-shaped graph) (Fig. 3).In addition, we found that the inflection point of serum calcium was 8.2 and 10.4 mg/dL using a recursive algorithm.Then, we calculated the OR and CI on the left and right of the inflection point.The results showed that the OR was 0.53 on the left side of the 8.2 mg/dL (95% CI 0.24, 0.67) (P < 0.0001).In addition, when serum calcium was < 8.2 mg/dL, a 1-unit (× 1 mg/dL) decrease in serum calcium was associated with a 47% increase in the incidence of cardiac arrest in stroke patients.Interestingly, the OR was 2.37 on the right side of the 10.4 mg/dL (95% CI 1.58, 3.57) (P < 0.0001), a 1-unit (× 1 mg/dL) increase in serum calcium was associated with a 137% increase in the incidence of cardiac arrest in stroke patients (Table 4).
As shown in Table 5, we conducted subgroup analysis to investigate potential additional risk factors that could influence the relationship between serum calcium and SCA in stroke patients.We examined the impact of gender, stroke type, renal function, and end-stage renal disease as stratification factors.However, our analysis revealed that males, ischemic stroke, creatinine levels, and end-stage renal disease all played significant roles in affecting the relationship between serum calcium and SCA in stroke patients.

Discussion
This retrospective cohort study aimed to investigate the association between serum calcium and SCA in stroke patients.The main findings are as follows: Serum calcium and ACSC are independent risk factors for SCA occurrence in ICU stroke patients.This study observed, for the first time, a non-linear relationship between serum calcium and the risk of SCA during the hospitalization of stroke patients.We identified the inflection points for serum calcium as 8.2 mg/dL and 10.4 mg/dL.It is worth noting that maintaining serum calcium levels within the range of 8.2-10.4mg/dL may significantly reduce the incidence of cardiac arrest in stroke patients.Subgroup analysis revealed that gender, ischemic stroke, creatinine levels, and end-stage renal disease all played significant roles in affecting the relationship between serum calcium and SCA in stroke patients.Calcium homeostasis disorders can contribute to various cardiovascular diseases.Recent cohort studies have examined the connection between calcium levels and both cardiovascular and all-cause mortality.Interestingly, both high and low calcium levels have been linked to an increased risk of cardiovascular events.Both high and low levels of calcium were associated with an increase in cardiovascular events.Yamaguchi et al. 22 identified  www.nature.com/scientificreports/hypocalcemia as a significant risk factor for mortality and cardiovascular events among incident hemodialysis patients.Similarly, Similarly, Miura and associates 23 conducted a study that reviewed a group with low calcium levels, revealing significantly higher rates of cardiac and all-cause mortality, along with indications of heart and kidney damage in patients with heart failure and chronic kidney disease.Moreover, it was observed that lower calcium levels upon admission were associated with elevated in-hospital mortality in patients with ST-segment elevation myocardial infarction 24 .These findings align closely with the results of our study, where it is evident in Table 1 that patients with lower calcium levels (Q1) experienced higher in-hospital mortality.
In another study reported by Grandi et al., a cohort of patients with stable coronary artery disease (CAD) was followed for 8 years.They reported that patients with higher baseline serum calcium levels had significantly higher all-cause mortality.Grandi et al. suggested that higher calcium levels may contribute to the progression of vascular calcification and are associated with an increased risk of adverse cardiovascular events 25 .Additionally, Lundgren et al. reported that mild hypercalcemia was associated with premature death from cardiovascular disease 26 .In contrast to the studies, our study reached a different conclusion because the patients in our study hardly exceeded the upper limit of normal calcium levels.Furthermore, a recent study reported that lower   www.nature.com/scientificreports/serum calcium levels increased the risk of cardiovascular death in men and decreased the risk in women 27 .In our study, we also observed that male patients were more likely to experience SCA.Additionally, we found that the type of stroke and kidney function status could also influence the relationship between serum calcium and SCA in stroke patients.Yarmohammadi et al. 10 found that low serum calcium levels are independently associated with an increased risk of sudden cardiac arrest (SCA) in the general population.For each decrease of one unit in calcium, there was a 1.6-fold increase in the odds of SCA (OR 1.63, 95% CI 1.06-2.51).This is in line with our study findings.However, their study specifically recruited high-risk groups for cardiac disease in both the experimental and control groups, leading to more than 80% of individuals in the "general population", in both groups, having coronary heart disease.Furthermore, their study included some patients with renal insufficiency and those undergoing hemodialysis.Therefore, their study results may not fully represent all population groups, especially hospitalized stroke patients.Hypocalcemia is extremely common in hospitalized patients (up to 88%) and correlates with the severity of the disease 28 .Stroke, with higher mortality, is a critical illness, that often has a variety of cardiovascular diseases and cardiac complications.Due to increasingly severe conditions, an increasing proportion of acute stroke patients are being admitted to an ICU 29 .It is obvious that stroke patients may also have hypocalcemia.Hence, further investigating the relationship between serum calcium and SCA may be favorable for stroke patients.
The results of this study are consistent with a previous study 10 .This study demonstrated that baseline serum calcium levels were associated with the occurrence of sudden cardiac arrest (SCA) in patients with acute stroke.When serum calcium levels were categorized into tertiles, our results showed that the group with the lowest serum calcium levels had a significantly increased incidence of cardiac arrest.The trend in effect sizes between the groups was equidistant when serum calcium was treated as a categorical variable.The trend P-value was consistent with the result when serum calcium was analyzed as a continuous variable.This finding is also in line with a recent study 11 .However, previous studies did not specify whether the relationship between serum calcium and cardiac arrest was linear or nonlinear, and the study population was the general population, limiting the significance of the findings.In this study, we used a generalized additive model (GAM) and smooth curve fitting to demonstrate a nonlinear relationship between serum calcium and the risk of SCA in stroke patients.After adjusting for confounding factors, the inflection point of serum calcium was determined to be 8.2 mg/dL and 10.4 mmol/L.When serum calcium was below 8.2 mg/dL or above 10.4 mg/dL, the risk of SCA in stroke patients was significantly increased.This finding provides valuable guidance for the prevention of SCA in ICU patients.
This study has some notable strengths.First, the reliability of the data benefits from the relatively large sample size, as it is a multicenter study covering patient data from 208 hospitals in the United States.Second, we observed a nonlinear relationship between serum calcium and the risk of in-hospital sudden cardiac arrest (SCA) in stroke patients.Additionally, we found that maintaining serum calcium within the range of 8.2-10.4mg/dL may significantly reduce the incidence of cardiac arrest in stroke patients.
However, this study also has some potential limitations.Firstly, it is a retrospective analysis study, which may not eliminate potential confounding factors.Secondly, the database used for this study only recorded serum calcium levels at the time of admission and did not provide data for multiple measurements.Nevertheless, future research will focus on studying the impact of changes in serum calcium on the occurrence of sudden cardiac arrest in stroke patients.Furthermore, all patients included in this study came from intensive care units, so this conclusion may not be applicable to patients in general wards.Additionally, due to the database providing only short-term follow-up data, we cannot determine long-term outcomes.Finally, the relationship between serum calcium and the risk of in-hospital SCA in stroke patients may not necessarily be causal, and longitudinal analysis is needed to reveal more causative insights.

Conclusions
Serum calcium was an independent risk factor for the incidence of SCA poststroke in critically ill stroke patients.For the first time, we report a nonlinear relationship between serum calcium levels and in-hospital SCA risk in stroke patients.Maintaining serum calcium levels within the range of 8.2-10.4mg/dL may significantly reduce the incidence of cardiac arrest in stroke patients.

Data source
The data analyzed in this study were extracted from the eICU-CRD, a multicenter intensive care unit database containing over 200,000 cases 16,17 .As a multicenter database, the e-ICU platform documents the electronic medical records of patients from 208 hospitals in the United States from 2014 to 2015.The use of this database was approved by the Institutional Review Board of the Massachusetts Institute of Technology (Cambridge, Massachusetts, USA).One author (Zhenhua Huang) obtained access rights and was responsible for data extraction (certification number: 49995491).All methods were performed in accordance with the eICU-CRD relevant guidelines and regulations.

Study population
Patients with a primary diagnosis of brain stroke, were grouped into 3 categories: ischemic stroke (IS) group, hemorrhagic stroke (HS) group, and others group 18 .Sudden cardiac arrest (SCA) was defined as a sudden unexpected pulseless condition and noncardiac etiologies 19 .All patients included were admitted for stroke.All enrolled patients signed an informed consent form, according to the World Medical Association Declaration of Helsinki, revised in 2013.Cardiac arrest occurs during hospitalization.This study initially included 11,107 www.nature.com/scientificreports/Student's t test or one-way ANOVA.Nonnormal data are expressed as the median with interquartile range (IQR) and were compared using the Wilcoxon rank-sum test.Variables with a two-tailed P value < 0.05 were statistically significant and were included in the regression model.Multivariate-adjusted odds ratios (OR) and 95% confidence intervals (CI) for the study outcomes and calcium (1 unit and tertiles) were calculated by logistic regression analysis.Following covariate screening, we built three different models using both univariate and multivariate binary logistic regression models to study the relationship between serum calcium and in-hospital SCA poststroke.The model was as follows: (i) nonadjusted model (unadjusted covariates); (ii) minimum adjustment model (Model I: adjusted for age, sex, and ethnicity); (iii) fully adjusted model (age, sex, ethnicity, AF, CHF, ACS, COPD, diabetes, hypertension, GCS, Hb, Scr, and ALB).All P values were two-tailed and a P value < 0.05 was considered statistically significant.The smoothing curves and forest plots were illustrated by EmpowerStats (X&Y Solutions, Inc., Boston, MA).

Figure 1 .
Figure 1.Distribution of GCS.It follows a non-normal distribution, ranging from 3 to 15.

Figure 2 .
Figure 2. Stratification of stroke severity in stroke patients.As shown in the figure, severe strokes account for 15.84%, moderate strokes make up 16.07%, and the majority are mild cases, representing 68.09% of the total.

Figure 3 .
Figure 3.The nonlinear relationship of serum calcium with in-hospital SCA in stroke patients.The smoothing splines were a generated utilizing generalized additive model and adjusted for age, sex, ethnicity, AF, CHF, ACS, COPD, diabetes, hypertension, GCS, Hb, Scr, and ALB.The red line indicates the risk of cardiac arrest and the blue dotted line indicates the 95% confidence interval. https://doi.org/10.1038/s41598-023-51027-x

Table 1 .
The baseline characteristics of participants.Continuous variables are summarized as mean (SD) or median (quartile interval); categorical variables are presented as percentages (%).BMI body mass index, BUN blood urea nitrogen, Scr serum creatinine, RBC red blood cell, Hb hemoglobin, ACS acute coronary syndrome, AF atrial fibrillation, CHF congestive heart-failure, AMI acute myocardial infarction, COPD chronic obstructive pulmonary disease, ICU intensive care unit, PC platelet count, ACSC albumin-corrected serum calcium.

Table 2 .
Factors influencing risk of SCA in stroke patients analyzed by univariate analysis.

Table 3 .
Relationship between serum calcium and cardiac arrest with stroke patients in different models.Non-adjusted model: no covariates were adjusted for.Adjusted model I: we only adjusted for age, sex, and ethnicity.Adjusted model II: we adjusted for age, sex, ethnicity, AF, CHF, ACS, COPD, diabetes, hypertension, GCS, Hb, Scr, and ALB.

Table 4 .
The result of the two-piecewise linear regression model.

Table 5 .
Stratified associations between serum calcium and SCA in patients with stroke by type of stroke, sex, Scr and ESRD.ESRD end-stage renal disease.